麻豆传媒

GAITHERSBURG, Md. -- The FDA continues to find a signal of excess long-term mortality with paclitaxel-coated balloons and stents in peripheral artery disease, agency staff said Wednesday morning, kicking off a on the matter.

Updated death rates, based on data collected from industry since the FDA's , showed a disadvantage for as-treated paclitaxel device recipients that begins to emerge at year 3 compared with control groups across four pivotal randomized trials (RR 1.46 on fixed-effects model, 95% CI 1.01-2.11).

The difference persisted to year 5 (RR 1.57, 95% CI 1.16-2.13) among the three trials with sufficient follow-up data, according to Adrijo Chakraborty, PhD, an FDA statistician who spoke before the agency's Circulatory System Devices Panel.

Thus, the updated FDA analyses supported the late mortality signal first reported in December in a .

However, patient-level data were still lacking in getting these new numbers, said Yu Zhao, PhD, another FDA statistician.

Manufacturers, however, argued that their patient-level data suggest no significant mortality difference between groups nor any paclitaxel dose-mortality relationship after correcting for crossover and taking into account registry information from the real world.

"We're being subjected to a forest of dueling numbers," lamented panelist John Hirshfeld, MD, of Penn Heart and Vascular Center in Philadelphia.

The (n=474), (n=476), (n=330), and (n=300) trials probed by the FDA had assessed the paclitaxel-coated Zilver PTX stent, Lutonix balloon, IN.PACT Admiral balloon, and Stellarex balloon, respectively, for use in the femoropopliteal arteries.

ILLUMENATE was limited to 3-year follow-up, whereas the other trials went up to 5 years. ZILVER PTX was the sole investigation to allow patients to cross over after their assigned procedures.

Notably, in the IN.PACT studies, the survival differential for paclitaxel recipients was markedly worse in the U.S. than in Europe, according to Zhao. No such interaction was observed in the other three trials.

Event reporting was generally an issue: The FDA found that two trials of similar size and enrollment criteria yielded 200 adverse events in one but more than 1,000 in the other during the same period of time, noted Donna Buckley, MD, an interventional radiologist at MedStar Georgetown University Hospital in Washington, D.C., who spoke during the agency's presentation.

Deaths from all cardiovascular and non-cardiovascular causes trended higher with the paclitaxel devices, with the exceptions of infection and trauma. Among malignancies, no particular cancer type emerged as especially common.

Ultimately, there is no spike in any specific adverse event to suggest a mechanism for the observed increase in mortality, Buckley told the audience.

The FDA advisory panel will reconvene Thursday to discuss a potential dose effect from paclitaxel exposure, the benefit-risk profile of these devices, and recommended next steps.

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